Abstract
Alphaviruses can infect a broad range of vertebrate hosts, including birds, horses, primates, and humans, in which infection can lead to rash, fever, encephalitis, and arthralgia or arthritis. They are most often transmitted by mosquitoes in which they establish persistent, asymptomatic infections. Currently, there are no vaccines or antiviral therapies for any alphavirus. Several Old World alphaviruses, including Semliki Forest virus, Ross River virus and chikungunya virus, activate or hyperactivate the phosphatidylinositol-3-kinase (PI3K)-AKT pathway in vertebrate cells, potentially influencing many cellular processes, including survival, proliferation, metabolism and autophagy. Inhibition of PI3K or AKT inhibits replication of several alphaviruses either in vitro or in vivo, indicating the importance for viral replication. In this review, we discuss what is known about the mechanism(s) of activation of the pathway during infection and describe those effects of PI3K-AKT activation which could be of advantage to the alphaviruses. Such knowledge may be useful for the identification and development of therapies.
Highlights
We describe the activation of the phosphatidylinositol 3-kinases (PI3K)-AKT pathway by alphaviruses and the consequent cellular effects
Class 1A PI3Ks are activated by receptor tyrosine kinases (RTK) or G protein-coupled receptors (GPCR) after binding of growth factors, either directly or indirectly via activation of the small GTPase RAS [5] (Figure 1)
YXXM-containing proteins, we propose that the tyrosine residue is phosphorylated by a plasma membrane (PM)-localised cellular tyrosine kinase, but the identity of such a kinase(s) is not known
Summary
Viruses activate metabolic pathways in order to meet their needs for production of appropriate macromolecules. AKT signalling suppresses expression of FoxO signalling viatargets these involved multifunctional targets promotes cellcell-cycle survival,arrest, growth and proliferation and. These include in the induction of apoptosis, catabolic metabolism and steers cellular metabolism towards anabolism. PI3K-AKT signalling via these multifunctional targets promotes cell survival, Cells 2020, 9, 970 growth and proliferation and steers cellular metabolism towards anabolism. The promotes other.The. ForPI3K-AKT example, MEK promotes membrane localisation of RAF-MEK-ERK the phosphatasepathway and tensin homologue cell survival andit growth and the twoPIP3 pathways have co-regulated proteins and negatively regulate (PTEN), where dephosphorylates and inhibits. Through a translational modifications (including (de)phosphorylation acetylation) variety of downstream targets of mTORC1, AKT signalling isand inhibited [7]. The nsP3 HVD is a hub for interactions with multiple cellular proteins and can modulate multiple cellular pathways during infection [11]
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